Apolipoprotein C-III (also called APOC3, APOC-III, ApoCIII, and APO C-III) is a constituent of HDL and of triglyceride (TG)-rich lipoproteins. ApoCIII slows clearance of TG-rich lipoproteins by inhibiting lipolysis through inhibition of lipoprotein lipase (LPL) and through interfering with lipoprotein binding to cell-surface glycosaminoglycan matrix (Shachter, Curr. Opin. Lipidol, 2001, 12, 297-304).
Elevated ApoCIII levels have been associated with elevated TG levels, elevated hepatic insulin resistance and diseases such as cardiovascular disease, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), obesity and diabetes (Chan et al., Int J Clin Pract, 2008, 62:799-809; Onat et al., Atherosclerosis, 2003, 168:81-89; Mendivil et al., Circulation, 2011, 124:2065-2072; Mauger et al., J. Lipid Res, 2006, 47: 1212-1218; Chan et al., Clin. Chem, 2002. 278-283; Ooi et al., Clin. Sci, 2008, 114: 611-624; Davidsson et al., J. Lipid Res. 2005, 46: 1999-2006; Sacks et al., Circulation, 2000, 102: 1886-1892; Lee et al., Arterioscler Thromb Vasc Biol, 2003. 23: 853-858; Lee et al., Hepatology, 2011, 54:1650-1660) while a null mutation in human ApoCIII was found to confer a favorable plasma lipid profile and cardioprotection (Pollin et al., Science, 2008, 322:1702-1705) leading to the assumption that decreasing ApoCIII levels would ameliorate certain diseases associated with elevated ApoCIII or improve physiological markers of disease such as insulin resistance.
However, the relationship between ApoCIII and disease is complicated. For example, some studies have suggested that decreasing ApoCIII levels would not necessarily improve insulin resistance in a subject. Hypertriglyceridemic mice transgenic for the human ApoCIII gene were not found to be insulin resistant (Reaven et al., J. Lipid Res, 1994, 35:820-824). However, a different study in ApoCIII transgenic mice found severe hepatic insulin resistance but no peripheral insulin resistance change (Lee et al., Arterioscler Thromb Vasc Biol, 2003. 23: 853-858; Lee et al., Hepatology, 2011, 54:1650-1660). Further, in a mouse ApoCIII knockout model, obesity and insulin resistance was increased (Duivenvoorden et al., Diabetes, 2005, 54:664-671). Accordingly, further study is needed to determine whether the effects of decreasing ApoCIII levels would ameliorate diseases associated with elevated ApoCIII such as diabetes, or the risk of diabetes, or improve physiological markers of disease such as insulin resistance
Antisense technology is emerging as an effective means for reducing the expression of certain gene products and may prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of ApoCIII. Antisense compounds targeting ApoCIII and associated methods for inhibiting ApoCIII have been previously disclosed (see e.g., U.S. Pat. No. 7,598,227, U.S. Pat. No. 7,750,141, PCT publication WO 2004/093783 and PCT publication WO 2012/149495, all incorporated-by-reference herein). An antisense compound targeting ApoCIII, ISIS-APOCIIIRx, has been tested in a Phase I clinical trial and was shown to be safe. Currently, ISIS-APOCIIIRx is in Phase II clinical trials to assess its effectiveness in the treatment of hypertriglyceridemia. However, there is still a need to provide additional and more potent treatment options for subjects having, or have a risk for, diabetes.